Abstract 815: Improved tolerability and tumor specific delivery of a therapeutic bispecific T cell engager using a pH-sensitive nanoparticle platform
Authors: Qingtai Su, Stephen Gutowski, Gaurav Bharadwaj, Austin Burcham, Bhargavi Allu, Irina Kalashnikova, Zirong Chen, Ruolan Han, Jason B. Miller, Tian Zhao
Journal: Cancer Research (2023)

Abstract Bispecific antibodies are an emerging class of therapeutics for immune-oncology applications. T cell engagers (TCEs) target tumor-associated antigens (TAA) to eradicate cancer cells. TCEs for solid tumors have demonstrated encouraging preclinical efficacy but development has been challenging with dose-limiting toxicities due to on-target/off-tumor effect. To overcome the issue, we have developed ON-BOARD, an ultra-pH sensitive nanoparticle platform for masked and targeted delivery of payloads to the acidic tumor microenvironment (TME). Herein we report efficacious masked delivery of a TCE to tumors in mice using ON-BOARD demonstrating significantly improved tolerability and potential for clinical translation. TCEs were encapsulated in ON-BOARD nanoparticles and characterized for particle properties. The formulations were assessed in vitro under neutral or acid-activated conditions in TDCC assays. In vivo studies were performed in mice bearing “immune desert” pancreatic cancer. ON-BOARD tumor localization was measured by fluorescence while unencapsulated TCE and ON-BOARD/TCE pharmacokinetics was evaluated. PD studies evaluated immune-phenotype changes in tumors and draining lymph nodes, and systemic cytokine levels. Efficacy studies were performed in tumor-bearing mice comparing unencapsulated TCE to ON-BOARD-TCE as monotherapy and in combination with anti-4-1BB agonist therapy. ON-BOARD encapsulated TCEs have high encapsulation efficiency (&amp;gt;88%) in uniformly distributed stable particles (Dh&amp;lt;100nm). pH-specific and target-specific killing were confirmed in vitro in TDCC killing assays using a human gastric cancer cell line and a genetically engineered mouse pancreatic cancer cell line with 20 to 200-fold activation window between the acid-activated and intact formulations. In vivo, fluorescently labeled ON-BOARD nanoparticles localized to tumors in mice while ON-BOARD/TCE formulations demonstrated minimal payload leakage and mitigated payload degradation. ON-BOARD/TCE formulations showed favorable immunophenotype changes in tumors including increased CD8+, CD8+/T reg ratio and PD-1+Ki67+CD8+. ON-BOARD encapsulation also significantly improved TCE tolerability showing reduced body weight loss nadir (3% vs 17%) and reduced systemic proinflammatory cytokine response (IL-6, TNF, IFNγ, etc). When dosed in combination with anti-4-1BB agonist therapy in tumor-bearing animals, unencapsulated TCE induced 100% treatment-related animal death while ON-BOARD/TCE prevented animal death with minimum body weight loss. Furthermore, ON-BOARD/TCE with a4-1BB combo therapy showed 61% tumor growth inhibition in the “immune desert” pancreatic cancer model. The ON-BOARD platform demonstrated potential as an effective tool for masked tumor-specific delivery and improved tolerability of bispecific TCEs for cancer therapy. Citation Format: Qingtai Su, Stephen Gutowski, Gaurav Bharadwaj, Austin Burcham, Bhargavi Allu, Irina Kalashnikova, Zirong Chen, Ruolan Han, Jason B. Miller, Tian Zhao. Improved tolerability and tumor specific delivery of a therapeutic bispecific T cell engager using a pH-sensitive nanoparticle platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 815.